Protein kinase A
326707
214472613
2008-05-23T18:46:06Z
198.103.172.9
/* Overview table */
{{lowercase|title=cAMP-dependent protein kinase}}
In [[cell biology]], '''protein kinase A''', refers to a family of [[enzyme]]s whose activity is dependent on the level of [[cyclic AMP]] (cAMP) in the cell. '''PKA''' is also known as '''cAMP-dependent protein kinase''' {{EC number|2.7.11.11}}). Protein kinase A has several functions in the cell, including regulation of [[glycogen]], [[sugar]], and [[lipid]] [[metabolism]].
==Mechanism==
===Activation===
Each PKA is a [[holoenzyme]] that consists of two regulatory and two [[catalyst|catalytic]] [[subunit]]s. Under low levels of cAMP, the holoenzyme remains intact and is catalytically inactive. When the concentration of cAMP rises (e.g. activation of [[adenylate cyclase]]s by [[G protein-coupled receptor]]s coupled to [[Gs alpha subunit|G<sub>s</sub>]], inhibition of [[phosphodiesterase]]s which degrade cAMP), cAMP binds to the two [[binding site]]s on the regulatory subunits, which then undergo a [[Chemical conformation|conformation]]al change that releases the catalytic subunits.
===Catalysis===
The free catalytic subunits can then catalyse the transfer of ATP terminal phosphates to [[protein]] [[substrate (biochemistry)|substrate]]s at [[serine]], or [[threonine]] [[amino acid|residues]]. This [[phosphorylation]] usually results in a change in activity of the substrate. Since PKAs are present in a variety of cells and act on different substrates, PKA and cAMP regulation are involved in many different pathways.
The mechanisms of further effects may be divided into direct protein phosphorylation and protein synthesis:
*In direct protein phosphorylation PKA directly either increases or decreases the activity of a protein.
*In protein synthesis PKA first directly activates [[CREB]], which binds the [[cAMP response element]], altering the [[transcription]] and therefore the synthesis of the protein. This mechanism generally takes longer time (hours to days).
=== Inactivation ===
PKA is thus controlled by [[cyclic adenosine monophosphate|cAMP]]. Also, the catalytic subunit itself can be regulated by phosphorylation.
Downregulation of protein kinase A occurs by a feedback mechanism: one of the substrates that is activated by the kinase is a [[phosphodiesterase]], which quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A.
=== Anchorage ===
The 2 regulatory subunits of protein kinase A is important for localizing the kinase inside the cell, with the aid of [[A-kinase anchoring protein|A-kinase anchoring protein]] (AKAP), AKAP binds both to the regulatory subunits and to either a component of cytoskeleton structure or a membrane of an organelle, anchoring the enzyme complex to a particular subcellular compartment.
The catalytic function of protein kinase A would sometimes couple with the AKAP, binding PKA together with phosphodiesterase to form a complex that functions as a signal module. For example, an AKAP locating near the nucleus of a heart muscle cell, would bind to both PKA and phosphodiesterase that hydrolyzes cAMP. As phosphodiesterase contributes to the steady low concentration of cAMP in unstimulated cells, as the cell is stimulated, PKA is then responsible for the activation of phosphodiesterase (adjacent to PKA) in order to lower the concentration of cAMP, in this condition, as PKA and phosphodiesterase has formed a complex, the proximity increase the efficiency of PKA's activity.
==Function==
PKA phosphorylates other [[proteins]], altering their function. However, what proteins are available for phosphorylation depends on in what kind of cell the PKA activity is present, since protein composition varies from cell type to cell type. Thus, the effects of PKA varies with [[cell type]]:
===Overview table===
{| class="wikitable sortable"
|-
! [[Cell type]]
! Organ/system
! Stimulators <BR> [[ligands]] --> [[Gs alpha subunit|G<sub>s</sub>]]-[[G-protein coupled receptor|GPCR]]s <BR> or [[phosphodiesterase inhibitor|PDE inhibitors]]
! Inhibitors <BR> ligands --> [[Gi alpha subunit|G<sub>i</sub>]]-[[G-protein coupled receptor|GPCR]]s <BR> or [[phosphodiesterase|PDE]] stimulators
! Effects
|-
| [[adipocyte]] || ||
*[[epinephrine]] --> [[beta-adrenergic receptor|β-adrenergic receptor]]
*[[glucagon]] --> [[Glucagon receptor]]
|| ||
*enhance [[lipolysis]]
**stimulate [[lipase]]<ref name=Rang172> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 172</ref>
|-
| [[myocyte]] ([[skeletal muscle]]) || [[muscular system]] ||
*[[epinephrine]] --> [[beta-adrenergic receptor|β-adrenergic receptor]]
|| ||
*produce [[glucose]]
**stimulate [[glycogenolysis]]
***phosphorylate [[glycogen phosphorylase]] (activating it)<ref name=Rang172/>
***phosphorylate [[Acetyl-CoA carboxylase]] (inhibiting it)
**inhibit [[glycogenesis]]
***phosphorylate [[glycogen synthase]] (inhibiting it)<ref name=Rang172/>
**stimulate [[gluconeogenesis]]
***phosphorylate [[fructose 2,6-bisphosphatase]] (stimulating it)
**inhibit [[glycolysis]]
***phosphorylate [[pyruvate dehydrogenase]] (inhibiting it).
|-
| [[hepatocyte]] || [[liver]] ||
*[[epinephrine]] --> [[beta-adrenergic receptor|β-adrenergic receptor]]
*[[glucagon]] --> [[Glucagon receptor]]
|| ||
*produce [[glucose]]
**stimulate [[glycogenolysis]]
***phosphorylate [[glycogen phosphorylase]] (activating it)<ref name=Rang172/>
***phosphorylate [[Acetyl-CoA carboxylase]] (inhibiting it)
**inhibit [[glycogenesis]]
***phosphorylate [[glycogen synthase]] (inhibiting it)<ref name=Rang172/>
**stimulate [[gluconeogenesis]]
***phosphorylate [[fructose 2,6-bisphosphatase]] (stimulating it)
**inhibit [[glycolysis]]
***phosphorylate [[pyruvate dehydrogenase]] (inhibiting it).
|-
| [[neuron]]s in [[nucleus accumbens]] || [[nervous system]] || [[dopamine]] --> [[dopamine receptor]] || || Activate [[reward system]]
|-
| [[principal cell]]s in [[kidney]] || [[kidney]] ||
*[[Vasopressin]] --> [[Arginine vasopressin receptor 2|V2 receptor]]
*[[theophylline]] ([[phosphodiesterase inhibitor|PDE inhibitor]])
|| ||
*[[exocytosis]] of [[aquaporin 2]] to [[apical membrane]]. <ref name=boron842> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 842 </ref>
*synthesis of aquaporin 2 <ref name=boron842/>
*phosphorylation of aquaporin 2 (stimulating it)<ref name=boron842/>
|-
| [[myocyte]] ([[smooth muscle]]) || [[muscular system]] ||
*[[Beta-2 adrenergic receptor#agonists|β2 adrenergic agonists]] --> [[Beta-2 adrenergic receptor|β-2 adrenergic receptor]]
*[[histamine]] --> [[Histamine H2 receptor]]
*[[prostacyclin]] --> [[prostacyclin receptor]]
*[[Prostaglanding D2|Prostaglandin D<sub>2</sub>]] --> [[Prostaglandin D2 receptor|PGD<sub>2</sub> receptor]]
*[[Prostaglanding E2|Prostaglandin E<sub>2</sub>]] --> [[Prostaglandin E2 receptor|PGE<sub>2</sub> receptor]]
*[[Vasoactive intestinal peptide|VIP]] --> [[Vasoactive intestinal peptide receptor|VIP receptor]]
*L-[[Arginine]] --> [[imidazoline receptor|imidazoline]] and [[alpha-2 adrenergic receptor|α-2 receptor]]? ([[Gi alpha subunit|G<sub>i</sub>]]-coupled)
||
*[[muscarinic agonist]]s, e.g. [[acetylcholine]] --> [[Muscarinic acetylcholine receptor M2|muscarinic receptor M<sub>2</sub>]]
*[[Neuropeptide Y|NPY]] --> [[NPY receptor]]
|| [[Vasodilation]]
|-
| [[Thick ascending limb cell]] || [[kidney]] || [[Vasopressin]] --> [[Arginine vasopressin receptor 2|V2 receptor]] || || stimulate [[Na-K-2Cl symporter]] (perhaps only minor effect) <ref name=boron842> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 842 </ref>
|-
| [[Cortical collecting tubule cell]] || [[kidney]] || [[Vasopressin]] --> [[Arginine vasopressin receptor 2|V2 receptor]] || || stimulate [[Epithelial sodium channel]] (perhaps only minor effect) <ref name=boron842/>
|-
| [[Inner medullary collecting duct cell]] || [[kidney]] || [[Vasopressin]] --> [[Arginine vasopressin receptor 2|V2 receptor]] || ||
*stimulate [[urea transporter 1]]
*[[urea transporter 1]] exocytosis<ref name=boron844> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 844 </ref>
|-
| [[proximal convoluted tubule cell]] || [[kidney]] || [[Parathyroid hormone|PTH]] --> [[PTH receptor 1]] || || Inhibit [[NHE3]] --> ↓H<sup>+</sup> secretion<ref name=boron852> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 852 </ref>
|-
| [[juxtaglomerular cell]] || [[kidney]] ||
* [[adrenergic agonists]] --> [[β-receptor]]<ref name=boron867> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year=2003 |pages=1300 |isbn=1-4160-2328-3 |oclc= |doi=}} Page 867 </ref>
* agonists --> [[A2 receptor]]<ref name=boron867/>
*[[dopamine]] --> [[dopamine receptor]]<ref name=boron867/>
*[[glucagon]] --> [[glucagon receptor]]<ref name=boron867/>
|| || [[renin]] secretion
|-
|}
===In adipocytes, myocytes and hepatocytes ===
[[Epinephrine]] and [[glucagon]] affect the activity of protein kinase A by changing the levels of cAMP in a cell via the G-protein mechanism, using [[adenylate cyclase]]. Protein Kinase A acts to phosphorylate many enzymes important in metabolism. Protein kinase A phosphorylates [[Acetyl-CoA carboxylase]] and [[pyruvate dehydrogenase]]. Allosteric regulation of these enzymes in such a manner has an inhibitory effect. Insulin will increase the level of phosphorylation of these enzymes, which will divert acetyl-coA down the lipogenesis pathway. Glucagon has an [[antagonist]]ic effect.
===In nucleus accumbens neurons===
PKA helps transfer/translate the [[dopamine]] signal into cells. It has been found (postmortem) to be elevated in the brains of smokers, in the [[nucleus accumbens]], which mediates reward and motivation: a part of the brain acted on by "virtually all" recreational drugs; as well as "in the area of the midbrain that responds to dopamine, which acts as a 'reward chemical' in smokers and former smokers." <ref>[http://news.bbc.co.uk/2/hi/health/6378179.stm BBC NEWS | Health | Smoking alters brain 'like drugs'<!-- Bot generated title -->]</ref>
==See also==
* [[Protein kinase]]
* [[Signal transduction]]
* [[G protein-coupled receptor]]
* [[Serine/threonine-specific protein kinase]]
* [[Myosin light-chain kinase]]
* [[cAMP dependent pathway]]
==References==
<references/>
==External links==
* {{MeshName|Cyclic+AMP-Dependent+Protein+Kinases}}
{{Serine/threonine-specific protein kinases}}
[[Category:Signal transduction]]
[[Category:Protein kinases]]
[[Category:EC 2.7.11]]
[[de:Proteinkinase A]]
[[he:פרוטאין קינאז A]]
[[zh:蛋白激酶A]]